Throughout the evolution of life on Earth, the level of oxygen in the atmosphere increased. As a result, aerobic organisms had to develop efficient defense mechanisms in order to cope with increasing oxidative stress. The toxicity of oxygen is known to be due to the formation of reactive oxygen species (ROS) during the normal metabolism of a living organism. ROS include oxygen-derived free radicals and non-radical derivatives that are capable of inciting oxidative damage to biological structures. ROS have also been shown to be involved in more than one hundred different pathological syndromes and in the aging process.
There are several lines of defense against oxidative stress, including (i) macromolecules, such as enzymes, that can interact with ROS directly and remove them, or chelate metals and prevent the augmentation of oxidative damage; (ii) low molecular weight antioxidants that can interact directly with ROS, including both synthetic antioxidants and antioxidants from natural sources; and (iii) damage repair mechanisms.
In the last five years, in addition to the conventional idea that antioxidants interact with oxidants to minimize oxidative damage, a new and exciting role of these reduction-oxidation (redox) sensitive molecules (both oxidants and antioxidants) has become clear. These molecules function in a ubiquitous redox regulation of key biological processes such as immune response, cell-cell adhesion (e.g., atherosclerosis), cell proliferation, inflammation, metabolism, glucose uptake (diabetes) and programmed cell death (apoptosis). The basic regulation mechanism is due to the existence of redox-regulated amino acids in proteins, e.g., cysteine, tyrosine and methionine. Modifications of these amino acids by either oxidants or reducing agents can trigger or inhibit the biological function of a protein.
One of the most potent naturally occurring antioxidants known is lipoic acid (LA). .alpha.-Lipoic acid is also known as thioctic acid, 1,2-dithiolane-3-pentanoic acid, 1,2-dithiolane-3-valeric acid or 6,8-thioctic acid. .alpha.-Lipoic acid has a chiral carbon atom and occurs in two enantiomeric forms.
Biologically, lipoate exists as lipoamide in at least five proteins where it is covalently linked to a lysyl residue. Four of these proteins are found in .alpha.-ketoacid dehydrogenase complexes, the pyruvate dehydrogenase complex, the branched chain keto-acid dehydrogenase complex and the .alpha.-ketoglutarate dehydrogenase complex. Three lipoamide-containing proteins are present in the E2 enzyme dihydrolipoyl acyltransferase, which is different in each of the complexes and specific for the substrate of the complex. One lipoyl residue is found in protein X, which is the same in each complex. The fifty lipoamide residue is present in the glycine cleavage system.
Recently lipoic acid has been detected in the form of lipoyllysine in various natural sources. In the plant material studied, lipoyllysine content was highest in spinach 13.15 .mu.g/g dry weight; 92.51 .mu.g/mg protein). When expressed as weight per dry weight of lyophilized vegetables, the abundance of naturally existing lipoate in spinach was over three- and five-fold higher than that in broccoli and tomato, respectively. Lower concentrations of lipoyllysine were also detected in garden pea, Brussels sprouts and rice bran. Lipoyllysine concentration was below detection limits in acetone powders of banana, orange peel, soybean and horseradish, however.
In animal tissues, the abundance of lipoyllysine in bovine acetone powders can be represented in the following order: kidney&gt;heart&gt;liver&gt;spleen&gt;brain&gt;pancreas&gt;lung. The concentration of lipoyllysine in bovine kidney and heart were 2.64.+-.1.23 and 1.51.+-.0.75 .mu.g/g dry weight, respectively.
Lipoate in its reduced form as dihydrolipoate (DHLA) possesses two --SH groups which provide a very low oxidation potential to the molecule (-0.29 V). Thus, lipoic acid and the DHLA redox couple are excellent antioxidants capable of interacting with almost all forms of ROS, recycling other antioxidants and in addition reducing oxidized disulfide groups in biological systems. These molecules then may recuperate their biological reducing power and function. All of these qualities of LA make it also one of the most important molecules in redox signaling. A good example of this is the ability of this metabolically active compound to increase glucose uptake in an insulin mimic effect.
Various of the enantiomeric forms of .alpha.-lipoic acid, and combinations and derivatives thereof (including its reduced form), have been used to treat numerous conditions. For example, U.S. Pat. Nos. 5,650,429 and 5,532,269 disclose the use of lipoic acids in the treatment of circulatory disorders. U.S. Pat. No. 5,621,117 teaches that the D- and L-enantiomers of .alpha.-lipoic acid have different properties, with the D-enantiomer being primarily antiphlogistic and the L-enantiomer being mainly antinociceptive (analgesic). U.S. Pat. No. 5,569,670 discloses combinations of lipoic acids and vitamins in compositions useful for producing analgesic, anti-inflammatory, antinecrotic, anti-diabetic and other therapeutic effects. U.S. Pat. No. 5,334,612 describes certain alkylated derivatives of lipoic acid and their use in treatment of retroviral diseases. U.S. Pat. No. 5,084,481 discloses the use of reduced lipoic acid (DHLA) and salts thereof in treating inflammatory diseases. U.S. Pat. No. 5,693,664 discloses use of LA and DHLA in the treatment of diabetes. U.S. Pat. No. 5,508,275 discloses a variety of lipid-selective antioxidants, including lipoic acid derivatives.
ROS are also known to be capable of activating NF-kappa B, and it is believed that ROS are the final common signal for a number of stimuli that activate NF-kappa B. Sen and Packer, The FASEB Journal, Vol. 10, 709-720 (1996). The activation of NF-kappa B is believed to be involved, at least in part, in the causation or progression of a number of disease states. Packer et al., Advances in Pharmacology, Vol. 38, 79-101 (1997). The administration of antioxidant compositions including tocotrienyl lipoates has been proposed for regulating NF-kappa B activation in U.S. Provisional patent application Ser. No. 60/055,433, filed Aug. 4, 1997, which is incorporated herein in its entirety by reference.
Lipoic acid suffers from certain disadvantages, however. In particular, LA is reduced to DHLA within cells and then rapidly effluxed.
A need exists for an improved lipoic acid analog.
In addition to reactive oxygen species (ROS), reactive nitrogen species (RNS) such as nitrogen monoxide and byproducts thereof, in particular free radical byproducts thereof, have been implicated in inflammatory conditions such as diabetic neuropathy. Compositions which include lipoate derivatives, in particular tocotrienyl lipoates, have also been proposed for use in treating conditions in which RNS are involved, for example in U.S. Provisional application Ser. No. 60/055,433.
A need exists for improved compounds that are effective in treating conditions in which RNS are involved.